Alzheimer's disease (AD) is a progressive neurodegenerative disorder which is one of the most common causes of mental deterioration in elderly people, accounting for about 50-60% of the overall cases of dementia among persons over 65 years of age. Demographic data indicate that the percentage of elderly in the population is increasing.
Brain regions that are associated with higher mental functions, particularly the neocortex and hippocampus, are those most affected by the characteristic pathology of AD. This includes the extracellular deposits of β-amyloid (derived from amyloid precursor protein, APP) in senile plaques, intracellular formation of neurofibrillary tangles (containing an abnormally phosphorylated form of a microtubule associated protein, tau), and the loss of neuronal synapsis and pyramidal neurons.
Current treatment approaches in this disease continue being primarily symptomatic, with the major therapeutic strategy being based on the cholinergic hypothesis and specifically on acetylcholinesterase (AChE) inhibition. Over last decade, the cholinergic hypothesis of AD has launched on the market various cholinergic drugs primarily AChE inhibitors as tacrine, donepezil or rivastigmine, and more recently galanthamine, with modest improvement in the cognitive function of Alzheimer's patients. These compounds still present some undesired side effects such as nausea and vomiting.

The three dimensional structure of AChE, as determined by X-ray crystallography, revealed that its active site can apparently be reached only through a deep and narrow catalytic gorge. Inhibitors of AChE act on two target sites on the enzyme, the active site and the peripheral site. Inhibitors directed to the active site prevent the binding of a substrate molecule, or its hydrolysis, either by occupying the site with a high affinity molecule (tacrine) or by reacting irreversibly with the catalytic serine (organophosphates and carbamates). The peripheral site consists of a less well-defined area, located at the entrance of the catalytic gorge. Inhibitors that bind to that site include small molecules, such as propidium and peptide toxins as fasciculins. Bis-quaternary inhibitors as decamethonium, simultaneously bind to the active and peripheral sites, thus occupying the entire catalytic gorge.
Parallel to the development of antidementia drugs, research efforts have been focused, among others, on the therapeutic potential of AChE inhibitors to slow the disorder progression. This fact was based on a range of evidence, which showed that AChE has secondary non-cholinergic functions.
New evidence shows that AChE may have a direct role in neuronal differentiation. Additionally, the role of AChE in cell adhesion have been studied. The results indicate that AChE promotes neurite outgrowth in neuroblastoma cell line through a cell adhesive role.
Moreover, recent studies have shown that the peripheral anionic site of the AChE is involved in the neurotrophic activity of the enzyme and conclude that the adhesion function of AChE is located at the peripheral anionic site. This finding has implications, not only for our understanding of neural development and its disorders, but also for the treatment of neuroblastoma, the leukemias, and especially for Alzheimer's disease.
As it has been previously mentioned, senile plaques are one of pathological hallmarks in AD in which their main component is βA peptide. This is found as an aggregated poorly soluble form. In contrast soluble βA is identified normally circulating in human body fluids. Structural studies of βA showed that synthetic peptides containing the sequences 1-40 and 1-42 of βA can adopt two major conformational states in solution: an amyloidogenic conformer (βA ac) with a high content of β-sheet and partly resistant to proteases and a non-amyloidogenic conformer βA nac) with a random coil conformation or β-helix and protease-sensitive. AChE colocalized with βA peptide deposits present in the brain of Alzheimer's patients. It is postulated that AChE binds to a βA nac form acting as a pathological chaperone and inducing a conformational transition from βA nac into βA ac in vitro and therefore to amyloid fibrils. AChE directly promotes the assembly of βA peptide into amyloid fibrils forming stable βA-AChE complexes.
Considering the non-cholinergic aspects of the cholinergic enzyme AChE, their relationship to Alzheimer's hallmarks and the role of the peripheral site of AChE in all these functions, an attractive target for the design of new antidementia drugs emerged. Peripheral or dual site inhibitors of AChE may simultaneously alleviate the cognitive deficit in Alzheimer's patients and what it is more important, avoid the assembly of beta-amyloid which represents a new way to delay the neurodegenerative process.
Thus, ligands able to interact simultaneously with active and peripheral sites could implicate several advantages over the known inhibitors. On one hand, they should improve greatly the inhibitory potency and on the other had they should be involved in neurotrophic activity.
Very recently some compounds have been reported with both activities, see Piazzi L. et al., J. Med. Chem., 2003, 46, 2279-2282.
WO 03033489 describes piperidine derivatives having an effect of inhibiting acetylcholinesterase and aggregation of beta-amyloid.
WO 0117529 discloses halogen substituted tacrine or bistacrine derivatives for treating Alzheimer's disease. One of the subgroups presents an indole moiety connected to the tacrine through a short linker. For example, it describes the preparation of N-[2-(3-indolyl)ethyl]-6-chlorotacrine of formula:

WO 0117529 does not suggest a site of inhibition and does not give any activity data.
Castro, A.; Martinez, A. Mini Rev. Med. Chem., 2001, 1, 267-272 describe several families of peripheral and dual binding site AChE inhibitors, including some tacrine derivatives.
WO 04032929 discloses dual binding site AChE inhibitors containing a tacrine moiety connected through a linker to specified heterocycles such as a tacrine, an indanone or a thiadiazolidinone moiety.